본 발명은,약물전달 시스템의 전달체로 사용할 수 있고 생체내에서 분해가 가능한 열가소성 하이드로겔 합성에 관한 것으로서, 이 고분자의 구조적 특성은 양쪽 말단의 소수성 블럭과 중간부분의 친수성 블럭을 갖는 다중블럭 공중합체에 관한 것이다. 더욱 상세하게는, 친수성 부분으로 폴리에틸렌옥사이드(PEO)를 사용하고, 소수성 부분으로는 폴리락타이드(PLA), 폴리글라이콜라이드(PGA), 폴리락타이드 글라이콜라이드(PLGA), 폴리카프로락톤(PCL)등을 포함한 다중블럭 공중합체의 고분자로서, 친수성 고분자 블럭의 분자쇄 내에 에스테르 결합이나 아미드 결합등을 포함하여, 체내에 사용시 단순 가수분해 또는 가수분해 효소에 의해 작은 분자로 분해되어 신장을 통하여 체외로 바로 배출되거나 체내의 대사과정에 의해 소멸될 수 있는 인체에 무해한 열가소성.생분해성 약물전달용 고분자에 관한 것이다.The present invention relates to the synthesis of thermoplastic hydrogels that can be used as carriers for drug delivery systems and can be degraded in vivo, and the structural properties of these polymers are multiblock copolymers having hydrophobic blocks at both ends and hydrophilic blocks at the middle. It is about. More specifically, polyethylene oxide (PEO) is used as the hydrophilic portion, and polylactide (PLA), polyglycolide (PGA), polylactide glycolide (PLGA), and polycaprolactone (hydrophobic) are used. PCL) and other polymers of multiblock copolymers, including ester bonds and amide bonds in the molecular chain of the hydrophilic polymer block, when used in the body is broken down into small molecules by simple hydrolysis or hydrolase, The present invention relates to a thermoplastic, biodegradable drug delivery polymer that is harmless to the human body that can be directly discharged to the body or destroyed by metabolic processes in the body.
최근에는, 일정한 유효농도의 범위 내에서 또는 특정한 부위에서 약물의 방출이 조절되도록 하는 약물전달 시스템의 연구가 활발히 진행되지 않으며, 이러한 전달계의 전달체로 의료용 고분자 개발연구가 많이 이루어지고 있다. 지금까지 개발되어진 대부분의 고분자의 경우는 분자량이 작은 약물의 전달에만 한정되어 졌고, 비분해성 고분자의 경우는 체내에 사용하였을 때 일정기간이 지나면 물리적인 방법으로 이를 제거해야 하는 불편이 문제점으로 지적되어 왔다. 또한 이제까지 널리 연구되어온 하이드로겔의 경우, 분자내의 화학적 가교결합으로 인해 가공성이 현저히 떨어져서 적합한 제형을 만들기가 용이하지 않고, 비분해성 물질과 체내 사용이 의심스러운 물질로 인해 체내이식용 약물전달체로의 사용에는 많은 문제점이 제기되고 있다.In recent years, researches on drug delivery systems for controlling the release of drugs within a certain effective concentration range or at specific sites have not been actively conducted, and many researches for developing medical polymers have been made as delivery systems for such delivery systems. Most of the polymers developed so far have been limited to the delivery of low molecular weight drugs, and in the case of non-degradable polymers, the inconvenience of removing them by physical methods after a certain period of time has been pointed out as a problem. come. In addition, hydrogels, which have been widely studied until now, are not easily prepared due to chemical crosslinking in the molecule, which makes it difficult to form a suitable formulation. Many problems are raised.
이에 본 발명자들은 이러한 문제점들을 해결하기 위하여, 첫째 화학적 가교 결합이 없어서 용융가공 또는 용매 캐스팅 등의 쉬운 방법을 이용하여 적합한 제형으로의 가공이 용이하고, 둘째, 생체내에서 단순 가수분해 또는 가수분해 효소에 의해 독성이 없는 작은 분자로 분해되어, 체내의 대사과정에 참여하거나 신장을 통하여 체외로 바로 배출될 수 있는 열가소성.생분해성 고분자를 제조하게 되었다.Accordingly, in order to solve these problems, the present inventors, first, there is no chemical crosslinking so that it is easy to process into a suitable formulation using an easy method such as melt processing or solvent casting, and secondly, simple hydrolysis or hydrolase in vivo. It breaks down into small molecules that are not toxic and produces thermoplastic, biodegradable polymers that can participate in metabolic processes in the body or can be excreted immediately through the kidneys.
지금까지 알려진 생분해성 고분자로는, 지방족 폴리에스테르, 폴리오르소에스 폴리안하이드라이드, 폴리 α-아미노산, 폴리포스파겐, 폴리알킬시아노아크릴-레이트 등이다. 지방족 에스테르의 경우, 특히 폴리락타이드(PLA), 폴리글라이-콜라이드(PGA) 또는 폴리락타이드글라이콜라이드(PLGA)등은 미국 FDA에 의해 체내 사용시 부작용이 없다고 인정된 고분자들인데, 분자량이 작은 약물이나 물에 녹는 고분자량의 약물전달 시스템에 적용하여 왔다.Biodegradable polymers known so far are aliphatic polyesters, polyortho-polyshydrides, poly alpha -amino acids, polyphosphazenes, polyalkylcyanoacrylates, and the like. In the case of aliphatic esters, in particular polylactide (PLA), polyglycolide (PGA) or polylactideglycolide (PLGA) are polymers that have been recognized by the US FDA as having no side effects when used in the body. It has been applied to this small drug or high molecular weight drug delivery system.
최근에는 셀엔지니어링이나 DNA재조합 기술에 의해 인체에 필요한 폴리펩타이드나 단백질의 대량생산이 가능해짐에 따라 이들이 주요한 의약품으로 자리잡아가고 있다. 그러나 이러한 의약품들은, 수용성이면서도 고분자량이며 생체내 반감기가 짧고 주변 조건에 매우 불안정한 화합물로서 주로 주사에 의해 투여되고 있는데, 주사 이외의 알맞은 전달 경로를 찾는 것이 약물전달 분야에서 주요한 연구과제가 되고 있다. 단백질 의약품의 체내이식 전달 시스템에 대한 지방족 폴리에스터의 사용은, 단백질 약물 로오딩 과정에서의 어려움, 복잡한 방출 메카니즘, 낮은 분해속도 및 그들의 소수성 성질 등으로 인해 일정한 한계를 지니고 있다. 따라서 이런류의 약물전달 시스템의 전달체로서 보다 진보적인 분해성 물질의 개발이 필요하게 되었다.Recently, as cell engineering or DNA recombination technology enables mass production of polypeptides and proteins necessary for the human body, they are becoming a major medicine. However, these medicines are soluble, high molecular weight, short in vivo half-life and very unstable at ambient conditions, and are mainly administered by injection. Finding a suitable delivery route other than injection is a major research subject in the field of drug delivery. The use of aliphatic polyesters in the transdermal delivery system of protein pharmaceuticals has certain limitations due to difficulties in protein drug loading process, complex release mechanisms, low degradation rates and their hydrophobic properties and the like. Therefore, there is a need for the development of more advanced degradable substances as carriers of this kind of drug delivery system.
지금까지 알려진 블럭 공중합체로는 미국특허 제4,942,035호의 것이 있다. 이들의 고분자는, PLA/PEO/PLA 혹은 PGA/PEO/PGA형태의 블럭 공중합체로서, 친수성 부분으로는 큰 분자량의 폴리에틸렌옥사이드를 사용하였고, 소수성 부분으로는 폴리(D-, L-, or DL-락타이드), 폴리글라이콜라이드, 폴리(e-카프로락톤), 폴리(3-히드록시부틸산)등을 사용하였는데, 체내 사용시 고분자량의 PEO는 체외로의 배설이 어렵고, 생체내에서의 사용이 의심스러운 펜타에리트-리틀을 포함하고 있는 문제점이 있다.Block copolymers known to date are those of US Pat. No. 4,942,035. These polymers are block copolymers in the form of PLA / PEO / PLA or PGA / PEO / PGA, and high molecular weight polyethylene oxide is used as the hydrophilic part, and poly (D-, L-, or DL) is used as the hydrophobic part. -Lactide), polyglycolide, poly (e-caprolactone), poly (3-hydroxybutyl acid), etc., and high molecular weight PEO is difficult to excrete in vitro and There is a problem involving pentaeryt-little, which is suspect for use.
또한 미국특허 제4,716,302호에서는 이중블럭 공중합체나 삼중블럭 공중합체를 합성하였는데, 이들 블럭공중합체는 폴리알킬렌 옥사이드 폴리글라이콜라이드 및 트리메틸렌카보네이트 등을 포함하고 있다. 이들 고분자는 주로 코이팅 물질로 그 용도를 전개하였는데, 생체내 사용이 의심스럽거나 생체내에서 쉽게 분해할 수 없는 물질을 포함하는 결점이 있다.In addition, US Pat. No. 4,716,302 has synthesized a double block copolymer or a triple block copolymer, and these block copolymers include polyalkylene oxide polyglycolide and trimethylene carbonate. These polymers have developed their use mainly as coating materials, with the drawback of containing substances that are suspect for use in vivo or cannot be readily degraded in vivo.
이밖에도 친수성 성분으로서 폴리에틸렌글리콜을, 그리고 소수성 성분으로서 폴리락타이이드를 포함하는 블럭공중합체는, J.Pol. Sci.(A):Vol.27, 2151(1989)와 J.Pol. Sci.(A):Vol.39(1990)에 보고되어 있는데, 이들은 이들 두 성분을 공중합한 단순한 형태로 합성하여 약물전달 시스템에 사용하였다.In addition, block copolymers containing polyethylene glycol as a hydrophilic component and polylactide as a hydrophobic component are described in J. Pol. Sci. (A): Vol. 27, 2151 (1989) and J. Pol. Sci. (A): Vol. 39 (1990) reported that these two components were synthesized in a simple copolymerized form and used in drug delivery systems.
위에서 언급한 경우들은, 대부분 체외로의 배설이 어려운 고분자량의 폴리에틸렌글리콜을 사용하였고, 생체내에서 쉽게 분해가 되지 않거나 생체내 사용에 문제가 될 수 있는 물질들을 포함하고 있다.Most of the cases mentioned above use high molecular weight polyethylene glycol, which is difficult to excrete in vitro, and includes materials that are not easily degraded in vivo or may be problematic for in vivo use.
이러한 문제점들을 해결하기 위하여 본 발명자들은, 첫째, 화학적 가교결합이 없어서 가공이 용이하고, 둘째, 고분자량을 가지면서도 생체내 사용이 가능한, 다음과 같은 구조를 갖는 일반식(I)a 내지 (I)d로 표시되는 친수성 비분해성 고분자(A)와 소수성 생체분해성 고분자(B)를 결합시켜 합성된 생체분해성 약물 전달용 고분자를 완성하게 되었다.In order to solve these problems, the present inventors, firstly, there is no chemical cross-linking is easy to process, and second, general formula (I) a to (I) having a high molecular weight and can be used in vivo, By combining the hydrophilic non-degradable polymer (A) and the hydrophobic biodegradable polymer (B) represented by) d to complete the synthesized biodegradable drug delivery polymer.
상기식에서 A(―)는 폴리에틸렌옥사이드(PEO)또는 폴리에틸렌옥사이드/폴리프로필렌옥사이드 공중합체와 같은 친수성 비분해성 고분자이고,Wherein A (-) is a hydrophilic non-degradable polymer such as polyethylene oxide (PEO) or polyethylene oxide / polypropylene oxide copolymer,
B(----)는 폴리락타이드(PLA), 폴리글라이콜라이드(PGA), PLA/PGA 공중합체, 폴리카프로락톤(PCL), 폴리오르소에스터, 폴리안하이드라이드와 같은 소수성 생체 분해성 고분자 이고,B (----) is hydrophobic biodegradable such as polylactide (PLA), polyglycolide (PGA), PLA / PGA copolymer, polycaprolactone (PCL), polyorthoester, polyanhydride Polymer,
X는 아미드 결합, 에스테르 결합, 카바메이트 결합, 카보네이트 결합과 같은 생체내에서 분해되는 화학결합이고,X is a chemical bond that degrades in vivo, such as amide bonds, ester bonds, carbamate bonds, carbonate bonds,
Y는 아미드 결합, 에스테르 결합, 카바메이트 결합, 카보네이트 결합과 같은 A와 B, 또는 B들을 공유결합에 의해 연결하는 화학결합이며,Y is a chemical bond which connects A and B or B by covalent bonds such as amide bond, ester bond, carbamate bond, carbonate bond,
n은 0에서 20의 정수이다.n is an integer from 0 to 20.
친수성 비분해성 고분자로는, 분자량이 600에서 30,000사이의 폴리에틸렌옥사이드(PEO)또는 폴리에틸렌옥사이드/폴리프로필옥사이드 공중합체를 사용하는데, 2,000 에서 10,000 사이의 분자량을 사용하면 더욱 좋다. 2,000 이하의 저분자량을 사용하면 고분자의 유연성과 가공성이 떨어지고, 10,000 이상의 분자량을 사용하면 신장을 통한 배설에 어려움이 있다.As the hydrophilic non-degradable polymer, a molecular weight of 600 to 30,000 polyethylene oxide (PEO) or a polyethylene oxide / polypropyl oxide copolymer is used, and a molecular weight of 2,000 to 10,000 is more preferable. When using a low molecular weight of 2,000 or less, the flexibility and processability of the polymer is inferior, when using a molecular weight of 10,000 or more is difficult to excrete through the kidney.
생체내에서 분해되는 화학결합(X부분)에 대한 고분자량의 PEO 다중블럭을 합성하기 위해서는, 말단의 히드록실기가 다양한 관능기로 치환된 폴리에틸렌-글리콜(PEG)유도체를 사용하는데, 그 예로는To synthesize high molecular weight PEO multiblocks for chemical bonds (X moieties) that are degraded in vivo, polyethylene-glycol (PEG) derivatives in which terminal hydroxyl groups are substituted with various functional groups are used.
등이 있다. 이러한 PEG유도체들을 커플링하여 생체내에서 분해되는 화학결합에 의한 고분자량의 PEO 다중블럭을 합성하였다.Etc. These PEG derivatives were coupled to synthesize a high molecular weight PEO multiblock by chemical bonds that degrade in vivo.
소수성 생체분해성 고분자 블럭은 폴리락타이드(PLA), 폴리글라이콜라이드(PGA), 폴리카프로락톤(PCL), 또는 이들의 공중합체로 이루어지는데, 친수성 고분자 다중블럭과의 연결부분(Y)에 의해 다양한 수의 브랜치를 갖는 고분자를 얻을 수 있다.The hydrophobic biodegradable polymer block consists of polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL), or copolymers thereof, by means of a linkage (Y) with a hydrophilic polymer multiblock. Polymers having various numbers of branches can be obtained.
표1의 구성을 갖는 본 발명의 블럭 공중합체 중, 특히 PEO, PLA, PGA 및 PCL 을 포함하는 다중블럭 공중합체를 하기 구조식(I) 및 (I')으로 표현하였다.Among the block copolymers of the present invention having the structure of Table 1, in particular, multiblock copolymers including PEO, PLA, PGA and PCL are represented by the following structural formulas (I) and (I ′).
상기식에서 A는 친수성 고분자 다중블럭으로서, -[-(OCH2CH2)n-X]k-(CH2CH2O)n-이고, X는 -O(COCH2O)X-, -O[COCH(CH3)O]X-, -OCH2CONH-, -OCH2CH2CONH-, 또는 -OCONH-이며, Y는 -CHyNHCO-, Y'은 -CONHCHy-이고, R1및 R2는 수소원자이거나 메틸기이다.Wherein A is a hydrophilic polymer multiblock,-[-(OCH2 CH2 )n -X]k- (CH2 CH2 O) n-, and X is -O (COCH2 O)X- , -O[COCH (CH 3) O] X -, -OCH 2 and CONH-, -OCH2 CH2 CONH-, or -OCONH-, Y is -CHyNHCO-, Y 'is -CONHCHy -, and, R1 and R2 is a hydrogen atom or a methyl group.
x는 1에서 10의 정수이고, z는 1에서 5의 정수이다.x is an integer from 1 to 10 and z is an integer from 1 to 5.
y는 0, 1, 또는 2이며, 이때 ℓ은 각각 3, 2, 1의 값을 가진다.y is 0, 1, or 2, where l has a value of 3, 2, or 1, respectively.
m과 n은 20에서 500의 정수이고, k는 0에서 50의 정수이다.m and n are integers from 20 to 500 and k is an integer from 0 to 50.
본 발명을 더욱 상세히 설명하면 다음과 같다.The present invention is described in more detail as follows.
잘 건조된 반응용기에 분자량이 600 에서 30,000 범위에 있는 임의의 카르복시메틸 폴리에틸렌글리콜[HO2CCH2O(CH2CH2O)n-CH2CO2H] 1 당량과, 분자량이 600에서 30,000범위에 있는 임의의 폴리에틸렌글리콜 2당량, 디사이클로헥산-디아민 2당량을 적당한 유기용매하에서 반응한 후 여과하여 비극성 용매에 침전시켜, X부분이 에스테르 결합으로 이루어지는 A부분의 친수성 고분자 다중블럭이 합성하였다.1 equivalent of any carboxymethyl polyethylene glycol [HO2 CCH2 O (CH2 CH2 O)n -CH2 CO2 H] having a molecular weight in the range of 600 to 30,000 in a well-dried reaction vessel and a molecular weight of 600 to 30,000 2 equivalents of any polyethylene glycol in the range and 2 equivalents of dicyclohexane-diamine were reacted in a suitable organic solvent, and then filtered and precipitated in a nonpolar solvent to synthesize a hydrophilic polymer multiblock of A-part, wherein the X-part is an ester bond. .
또한, 충분히 건조된 반응용기에 분자량이 600에서 30,000 범위에 있는 임의의 폴리에틸렌글리콜(PEG) 1당량과, P-니트로페닐클로포메이트(NPC)나 카르보닐디이미다졸(CDI) 2.5당량을 잘 녹는 유기용매에 넣고서 녹인 후 트리에틸아민이나 피리딘 등의 염기를 2.5당량 가하여 반응시킨 후 여과하여 비극성 용매에 부으면, 말단의 히드록실 그룹이 NPC로 보호될 폴리에틸렌글리콜(NPC-PEG-NPC)이 침전되는데, 이것을 건조시킨 NPC-PEG-NPC 1당량과 600에서 30,000 범위에 있는 α-아미노, ω-히드록시 폴리에틸렌글리콜(H2N-PEG-OH) 2당량을 반응한 후 여과하여 비극성 용매에 침전시켜, X부분이 카바메이트 결합으로 이루어지는 A부분의 친수성 고분자 다중블럭이 합성하였다.In addition, 1 equivalent of any polyethylene glycol (PEG) and 2.5 equivalents of P-nitrophenylchloroformate (NPC) or carbonyldiimidazole (CDI) in a well-dried reaction vessel are well suited. After dissolving in a dissolved organic solvent and adding 2.5 equivalents of a base such as triethylamine or pyridine and then filtering and pouring into a non-polar solvent, polyethylene glycol (NPC-PEG-NPC) in which the hydroxyl group of the terminal is protected by NPC is precipitated. 1 equivalent of dried NPC-PEG-NPC and 2 equivalents of α-amino, ω-hydroxy polyethylene glycol (H2 N-PEG-OH) in the range of 600 to 30,000 were reacted, followed by filtration to precipitate in a nonpolar solvent. A portion of the hydrophilic polymer multiblock in which the X moiety consists of carbamate bonds was synthesized.
같은 방법으로, 말단의 히드록실기가 다양한 관능기로 치환된 폴리에틸렌글리콜(PEG) 유도체를 사용하여, X부분이 아마이드, 에스테르, 카보네이트 또는 카바메이트 등 생체내에서 분해될 수 있는 결합으로 이루어지는 A부분의 친수성 고분자 다중블럭을 합성하였다.In the same way, using a polyethylene glycol (PEG) derivative in which the terminal hydroxyl group is substituted with various functional groups, the X-part is composed of a bond that can be decomposed in vivo such as amide, ester, carbonate or carbamate. Hydrophilic polymer multiblock was synthesized.
위에서 합성한, A부분의 친수성 고분자 다중블럭의 말단 히드록실기를 P-니트로페닐클로포메이트(NPC)나 카르보닐디이미다졸(CDI)로 활성화시켜서, 트리스(히드록시알킬)아미노메탄과 극성용매에서 반응한 후 비극성 용매에 침전하면 양쪽 말단에 각각 3개의 히드록실기를 도입하였다. 이 히드록실기는 NMR상 양성자 피이크(3.22ppm)로 확인할 수 있었다.The terminal hydroxyl group of the A-hydrophilic polymer multiblock synthesized above was activated with P-nitrophenylchloroformate (NPC) or carbonyldiimidazole (CDI) to polarize with tris (hydroxyalkyl) aminomethane. After reacting in a solvent, precipitated in a non-polar solvent, three hydroxyl groups were introduced at both ends. This hydroxyl group was confirmed by proton peak (3.22 ppm) on NMR.
이렇게 얻어진, 말단에 여러개의 히드록실기를 갖는 다양한 분자량의 PEO 다중블럭 중합체를 1당량 취하여 잘 건조된 반응용기 내에 넣고서 THF 용매를 가하여 용해한 후, 0.05 노르말 내지 0.5 노르말의 칼륨-나프탈렌 용액을 히드록실기의 당량만큼 가하면 연녹색의 용액이 되었다가 색깔이 없어지는데, 이때 글라이콜라이드나 락타이드 등 소수성 고분자 블럭을 구성하는 모노머를 필요한 양만큼 가하여 중합하여, 본 발명의 생분해성 하이드로겔을 얻었다.Thus obtained, 1 equivalent of PEO multiblock polymer of various molecular weights having several hydroxyl groups at the end was put in a well-dried reaction vessel and dissolved by adding THF solvent, and then 0.05 to 0.5 normal potassium-naphthalene solution was dissolved. When the equivalent amount of the actual group is added, the solution becomes a pale green solution, and the color disappears. At this time, the monomer constituting the hydrophobic polymer block such as glycolide and lactide is added in an amount necessary to polymerize to obtain the biodegradable hydrogel of the present invention.
상술한 바와 같이 본 발명의 다중블럭 공중합체는, 중간 부분의 친수성 비분해성 고분자 블럭이 생체내에서 분해가능한 결합으로 연결된 다양한 분자량의 폴리에틸렌옥사이드 또는 폴리에틸렌옥사이드/폴리프로필렌옥사이드 공중합체로 구성되어 있고, 양쪽의 소수성 생체분해성 고분자 블럭은 여러개의 사슬로 이루어지는 폴리락타이드, 폴리글라이콜라이드, 폴리카프로락톤, 또는 이들의 공중합체로 구성되는데, 이들 각 블럭의 분자량이나 조성을 변화시킴으로써 다양한 특성을 지닌 열가소성 생분해성 하이드로겔을 제조할 수 있다. 따라서 본 발명에 의하면, 다양한 분자량의 공중합체를 쉽게 합성할 수 있으며, 고분자량이더라도 생체내에서 체외로 배설되는 작은 분자량으로 분해가 가능하고 또한 다양한 물리적.화학적 특성을 지닌, 종래의 고분자 제품보다 응용범위가 넓으면서 가공성이 향상된 하이드로겔을 제조할 수 있다.As described above, the multiblock copolymer of the present invention is composed of polyethylene oxide or polyethylene oxide / polypropylene oxide copolymer of various molecular weights in which an intermediate portion of a hydrophilic non-degradable polymer block is connected by a decomposable bond in vivo. The hydrophobic biodegradable polymer block of is composed of polylactide, polyglycolide, polycaprolactone, or copolymers thereof composed of several chains, and thermoplastic biodegradability having various properties by changing the molecular weight or composition of each block. Hydrogels can be prepared. Therefore, according to the present invention, copolymers of various molecular weights can be easily synthesized, and even high molecular weights can be decomposed into small molecular weights excreted in vitro and have various physical and chemical properties. It is possible to produce a hydrogel with a wide range and improved processability.
이하 본 발명을 실시예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by way of examples.
그러나, 본 발명이 실시예로 한정되는 것은 아니다.However, the present invention is not limited to the examples.
[실시예1]Example 1
충분히 건조된 반응용기에 분자량3,400인 폴리에틸렌글리콜(PEG) 1밀리몰, P-니트로페닐클로포메이트(NPC) 2.5 밀리몰, 건조된 THF 200ml 및 피리딘 2.5 밀리몰을 넣고서, 상온에서 24시간 저어준 후 여과하여 에테르에 침전시켜서 말단의 히드록실 그룹이 NPC로 보호된 폴리에틸렌글리콜(NPC-PEO-NPC)을 얻었다.Into a sufficiently dried reaction vessel, 1 mmol of polyethylene glycol (PEG) having a molecular weight of 3,400, 2.5 mmol of P-nitrophenyl chloroformate (NPC), 200 ml of dried THF and 2.5 mmol of pyridine, stirred at room temperature for 24 hours, and filtered Precipitation in ether gave polyethylene glycol (NPC-PEO-NPC) in which the terminal hydroxyl group was protected by NPC.
이것을 건조시킨 NPC-PEG-NPC 1밀리몰과 분자량 3400의 α-아미노, ω-히드록시 폴리에틸렌글리콜(H2N-PEG-OH) 2밀리몰을 잘 건조된 반응용기에 넣고서 48시간 반응하여 삼중블럭 PEO를 얻었으며, GPC에 의해 분석한 결과 삼중블럭 전환율은 79.2%이었다.1 mmol of dried NPC-PEG-NPC and 2 mmol of α-amino and ω-hydroxy polyethylene glycol (H2N-PEG-OH) having a molecular weight of 3400 were placed in a well-dried reaction vessel and reacted for 48 hours to obtain a triple block PEO. The triple block conversion was 79.2%.
이렇게 해서 얻은 삼중블럭 PEO 1밀리몰, P-니트로페닐클로포메이트(NPC) 3밀리몰 및 용매로 THF나 DMSO를 반응용기에 넣고 저어주면서, 염기로 피리딘 3밀리몰을 가하고서 상온에서 24시간 저어준 후 여과하여 에테르에 침전시켜서 말단의 히드록실 그룹이 NPC로 보호된 삼중블럭 PEO(NPC-PEO-PEO-PEO-NPC)를 얻었다.1 mmol of the triple block PEO thus obtained, 3 mmol of P-nitrophenyl chloroformate (NPC) and a solvent were added to THF or DMSO in a reaction vessel, and stirred with a base of 3 mmol of pyridine, followed by stirring at room temperature for 24 hours. Filtration followed by precipitation in ether afforded a triple block PEO (NPC-PEO-PEO-PEO-NPC) in which the terminal hydroxyl group was protected by NPC.
이것을 건조시킨 NPC-다중블럭 PEO 0.1밀리몰, 트리스(히드록시메틸) 아미노메탄 0.2밀리몰과 용매로 DMSO를 반응용기에 넣고서 24시간 반응한 후 에테르에 침전시켜 얻은 폴리머를 과량의 물로 씻어서 미반응한 트리스(히드록시메틸)아미노메탄을 제거하였다.Tris unreacted by washing the polymer obtained by washing with excess water in 0.1mg mol of dried NPC-multiblock PEO, 0.2 mmol of tris (hydroxymethyl) aminomethane and DMSO in a reaction vessel for 24 hours and then precipitated in ether. (Hydroxymethyl) aminomethane was removed.
NMR(DMSO-d6)의 분석결과 히드록실기의 양성자 피이크는 3.22ppm에서 나타났으며, 말단의 히드록실기를 아세틸기로 보호하고서 1% 페놀프탈레인을 지시약으로 사용하여 0.1N 수산화나트륨 용액으로 적정한 결과 4.8-5.2mg/g이었고, 분자량은 10600이었다.As a result of NMR (DMSO-d6 ), the proton peak of hydroxyl group was found at 3.22ppm, and titrated with 0.1N sodium hydroxide solution using 1% phenolphthalein as an indicator while protecting the terminal hydroxyl group with acetyl group. 4.8-5.2 mg / g, molecular weight 10600.
[실시예2]Example 2
각각 분자량 2000의 폴리에틸렌글리콜(PEG) 1밀리몰과 α-아미노, ω-히드록시 폴리에틸렌글리콜(H2N-PEG-OH) 2밀리몰을 사용한 것을 제외하고는 실시예 1과 같은 방법으로 반응시킨 결과, NMR상에서 히드록실기의 양성자 피이크는 3.22ppm에서 나타나고, 말단기는 5.0-5.5mg/g이었으며, 분자량은 6500이었다.The reaction was carried out in the same manner as in Example 1 except that 1 mmol of polyethylene glycol (PEG) having a molecular weight of 2000 and 2 mmol of α-amino and ω-hydroxy polyethylene glycol (H2N-PEG-OH) were used. The proton peak of the hydroxyl group appeared at 3.22 ppm, the terminal group was 5.0-5.5 mg / g, and the molecular weight was 6500.
[실시예3]Example 3
각각 분자량 3000의 폴리에틸렌글리콜(PEG) 1밀리몰과 α-아미노, ω-히드록시 폴리에틸렌글리콜(H2N-PEG-OH) 2밀리몰을 사용한 것을 제외하고는 실시예 1과 같은 방법으로 반응시킨 결과, NMR상에서 히드록실기의 양성자 피이크는 3.22ppm에서 나타나고, 말단기는 5.0-5.5mg/g이었으며, 분자량은 9500이었다.The reaction was carried out in the same manner as in Example 1, except that 1 mmol of polyethylene glycol (PEG) having a molecular weight of 3000 and 2 mmol of α-amino and ω-hydroxy polyethylene glycol (H2 N-PEG-OH) were used. On NMR, the proton peak of the hydroxyl group appeared at 3.22 ppm, the terminal group was 5.0-5.5 mg / g, and the molecular weight was 9500.
[실시예4]Example 4
각각 분자량 5000의 폴리에틸렌글리콜(PEG) 1밀리몰과 α-아미노, ω-히드록시 폴리에틸렌글리콜(H2N-PEG-OH) 2밀리몰을 사용한 것을 제외하고는 실시예 1과 같은 방법으로 반응시킨 결과, NMR상에서 히드록실기의 양성자 피이크는 3.22ppm에서 나타나고, 말단기는 4.0-4.5mg/g이었으며, 분자량은 15600이었다.The reaction was carried out in the same manner as in Example 1, except that 1 mmol of polyethylene glycol (PEG) having a molecular weight of 5,000 and 2 mmol of α-amino and ω-hydroxy polyethylene glycol (H2 N-PEG-OH) were used. On NMR, the proton peak of the hydroxyl group appeared at 3.22 ppm, the terminal group was 4.0-4.5 mg / g, and the molecular weight was 15600.
[실시예5]Example 5
잘 건조된 반응용기에 실시예 1에서 합성한 Tris-다중블럭 PEO(MW=10600) 0.1밀리몰을 넣고서 건조된 THF를 가하여 용해시키고서 0.1N농도의 칼륨-나프탈렌 용액을 0.6밀리몰 가하면 연녹색의 용액이 되었다가 색깔이 없어지는데, 이 때 아세트산 에틸에서 재결정하여 건조시킨 L-락타이드를 Tris-다중블럭 PEO의 무게만큼 THF에 녹여서 가하였다. 30분간 반응시킨 후, 에테르에 녹아 있는 소량의 초산을 가하여 반응을 종결하고, 차가운 메탄올에 침전시켜 냉장고에 하루동안 방치한 후, 여과하여 진공건조 하였다.0.1 mmol of Tris-multiblock PEO (MW = 10600) synthesized in Example 1 was added to a well-dried reaction vessel and dissolved by adding dry THF. Then, 0.6 mmol of potassium-naphthalene solution of 0.1 N concentration was added to give a pale green solution. Then, the color disappeared. At this time, L-lactide, which was recrystallized and dried in ethyl acetate, was dissolved in THF by the weight of Tris-multiblock PEO. After reacting for 30 minutes, a small amount of acetic acid dissolved in ether was added to terminate the reaction, precipitated in cold methanol, left in the refrigerator for one day, and then filtered and dried in vacuo.
얻어진 폴리머의 조성은 무게비로(Tris-다중블럭 PEO):(PLA)가 1: 1.06이었으며, NMR상에서 락타이드 양성자 피이크는 5.16,1.56ppm에서 나타나고, 옥시에틸렌(-CH2CH2O)의 양성자 피이크는 3.64ppm에서 나타났으며, 수평분자량은 22000이었다.The polymer composition obtained had a weight ratio of (Tris-multiblock PEO) :( PLA) of 1: 1.06, and lactide proton peaks appeared at 5.16,1.56 ppm on NMR, and were protons of oxyethylene (-CH2 CH2 O). The peak appeared at 3.64 ppm and the horizontal molecular weight was 22000.
[실시예6]Example 6
잘 건조된 반응용기에 실시예 2에서 합성한 Tris-다중블럭 PEO(MW=6500)와 L-락타이드를 무게비로 1:1.7 사용한 것을 제외하고는 실시예5와 같은 방법으로 반응시킨 결과, 얻어진 폴리머의 수평균 분자량은 18000이었다.The reaction was carried out in the same manner as in Example 5 except that Tris-multiblock PEO (MW = 6500) and L-lactide synthesized in Example 2 were used in a weight ratio of 1: 1.7 in a well-dried reaction vessel. The number average molecular weight of the polymer was 18000.
[실시예7]Example 7
잘 건조된 반응용기에 실시예 3에서 합성한 Tris-다중블럭 PEO(MW=9500)와 L-락타이드를 무게비로 1:1.7 사용한 것을 제외하고는 실시예5와 같은 방법으로 반응시킨 결과, 얻어진 폴리머의 수평균 분자량은 22000이었다.The reaction was carried out in the same manner as in Example 5, except that Tris-multiblock PEO (MW = 9500) synthesized in Example 3 and L-lactide were used in a weight ratio of 1: 1.7 in a well-dried reaction vessel. The number average molecular weight of the polymer was 22000.
[실시예8]Example 8
잘 건조된 반응용기에 실시예 4에서 합성한 Tris-다중블럭 PEO(MW=15600)와 L-락타이드를 무게비로 1:0.7 사용한 것을 제외하고는 실시예5와 같은 방법으로 반응시킨 결과, 얻어진 폴리머의 수평균 분자량은 17000이었다.The reaction was carried out in the same manner as in Example 5, except that Tris-multiblock PEO (MW = 15600) synthesized in Example 4 and L-lactide were used in a weight ratio of 1: 0.7 in a well-dried reaction vessel. The number average molecular weight of the polymer was 17000.
[실시예9]Example 9
충분히 건조된 반응용기에 각각 분자량이 3400인 α,ω-카르복시메틸 폴리에틸렌글리콜[HO2CCH2O(CH2CH2O)n-CH2CO2H] 1.5밀리몰,폴리에틸렌글리콜(PEG) 3밀리몰, 및 용매로 THF를 가하고서 상온에서 24시간 저어준 후 여과하여 에테르에 침전시켜서, 에테르 결합으로 연결된 삼중블럭 PEO를 얻었다.1.5 mmol of α, ω-carboxymethyl polyethylene glycol [HO2 CCH2 O (CH2 CH2 O)n -CH2 CO2 H], 3 mmol of polyethylene glycol (PEG), each having a molecular weight of 3400 in a sufficiently dried reaction vessel. THF was added to the solvent, and the mixture was stirred at room temperature for 24 hours, and then filtered and precipitated in ether to obtain a triple block PEO linked by ether bonds.
이것을 건조한 삼중블럭 PEO 1밀리몰, P-니트로페닐클로포메이트(NPC) 2밀리몰 피리딘 2밀리몰 및 용매로 THF를 넣고서 48시간 동안 저어준 후 여과하여 에테르에 침전시켜서 말단의 히드록실 그룹이 NPC로 보호된 삼중블럭 PEO(NPC-PEO-PEO-PEO-NPC)를 얻었다. 이것을 건조시킨 NPC-다중블럭 PEO 0.1밀리몰, 트리스(히드록시메틸) 아미노메탄 0.2밀리몰과 용매로 DMSO를 반응용기에 넣고서 24시간 반응한 후 에테르에 침전시켜 얻은 폴리머를 과량의 물로 씻어서 미반응한 트리스(히드록시메틸)아미노메탄을 제거하였다.1 mmol of dried triblock PEO, 2 mmol of P-nitrophenylchloroformate (NPC) and 2 mmol of pyridine, and THF as a solvent were stirred for 48 hours, followed by filtration and precipitation in ether to protect the hydroxyl group of the terminal with NPC. The obtained triple block PEO (NPC-PEO-PEO-PEO-NPC) was obtained. Tris unreacted by washing the polymer obtained by washing with excess water in 0.1mg mol of dried NPC-multiblock PEO, 0.2 mmol of tris (hydroxymethyl) aminomethane and DMSO in a reaction vessel for 24 hours and then precipitated in ether. (Hydroxymethyl) aminomethane was removed.
NMR(DMSO-d6)의 분석결과 히드록실기의 양성자 피이크는 3.22ppm, -OCH2C-의 양성자 피이크는 5.19ppm에서 나타났으며, 히드록실 말단기는 4.7-5.0mg/g이었고, 분자량은 10500이었다.As a result of NMR (DMSO-d6 ), the proton peak of hydroxyl group was 3.22ppm, the proton peak of -OCH2C- was 5.19ppm, the hydroxyl end group was 4.7-5.0mg / g, and molecular weight was 10500 It was.
[실시예10]Example 10
각각 분자량이 2000인 α,ω-카르복시메틸 폴리에틸렌글리콜과 폴리에틸렌글리콜을 사용한 것을 제외하고는 실시예9와 같은 방법으로 반응시킨 결과, NMR상에서 히드록실기의 양성자 피이크는 3.21ppm, -OCH2C-의 양성자 피이크는 5.20ppm에서 나타났으며, 히드록실 말단기는 5.8-6.2mg/g이었고, 분자량은 6600이었다.The reaction was carried out in the same manner as in Example 9 except that α, ω-carboxymethyl polyethyleneglycol having a molecular weight of 2000 and polyethyleneglycol were used, respectively, and the proton peak of the hydroxyl group on the NMR was 3.21 ppm and -OCH2C-. The peak appeared at 5.20 ppm, the hydroxyl end group was 5.8-6.2 mg / g and the molecular weight was 6600.
[실시예11]Example 11
각각 분자량이 3000인 α,ω-카르복시메틸 폴리에틸렌글리콜과 폴리에틸렌글리콜을 사용한 것을 제외하고는 실시예9와 같은 방법으로 반응시킨 결과, NMR상에서 히드록실기의 양성자 피이크는 3.21ppm, -OCH2C-의 양성자 피이크는 5.21ppm에서 나타났으며, 히드록실 말단기는 4.6-5.1mg/g이었고, 분자량은 9300이었다.The reaction was carried out in the same manner as in Example 9 except that α, ω-carboxymethyl polyethyleneglycol having a molecular weight of 3000 and polyethyleneglycol were used, respectively, and the proton peak of the hydroxyl group on the NMR was 3.21 ppm and -OCH2C-. The peak appeared at 5.21 ppm, the hydroxyl end group was 4.6-5.1 mg / g and the molecular weight was 9300.
[실시예12]Example 12
각각 분자량이 5000인 α,ω-카르복시메틸 폴리에틸렌글리콜과 폴리에틸렌글리콜을 사용한 것을 제외하고는 실시예9와 같은 방법으로 반응시킨 결과, NMR상에서 히드록실기의 양성자 피이크는 3.21ppm, -OCH2C-의 양성자 피이크는 5.21ppm에서 나타났으며, 히드록실 말단기는 4.5-4.5mg/g이었고, 분자량은 15400이었다.The reaction was carried out in the same manner as in Example 9 except that α, ω-carboxymethyl polyethylene glycol and polyethylene glycol each having a molecular weight of 5000 were used. As a result, the proton peaks of hydroxyl groups on NMR were 3.21 ppm and -OCH2C-. The peak appeared at 5.21 ppm, the hydroxyl end group was 4.5-4.5 mg / g and the molecular weight was 15400.
[실시예13]Example 13
잘 건조된 반응용기에 실시예 9에서 합성한 Tris-다중블럭 PEO(MW=10500) 0.1밀리몰을 넣고서 건조된 THF를 가하여 용해시키고서 0.1N농도의 칼륨-나프탈렌 용액을 0.6밀리몰 가하면 연녹색의 용액이 되었다가 색깔이 없어지는데, 이 때 아세트산 에틸에서 재결정하여 건조시킨 L-락타이드를 Tris-다중블럭 PEO의 무게의 1.5배만큼 THF에 녹아서 가하였다. 30분간 반응시킨 후, 에테르에 녹아 있는 소량의 초산을 가하여 반응을 종결하고, 차가운 메탄올에 침전시켜 냉장고에 하루동안 방치한 후, 여과하여 진공건조 하였다.0.1 mmol of Tris-multiblock PEO (MW = 10500) synthesized in Example 9 was added to a well-dried reaction vessel and dissolved by adding dry THF. Then, 0.6 mmol of potassium-naphthalene solution of 0.1 N concentration was added to give a pale green solution. Then, the color disappeared. At this time, L-lactide, which was recrystallized from ethyl acetate and dried, was added to THF by dissolving 1.5 times the weight of Tris-multiblock PEO. After reacting for 30 minutes, a small amount of acetic acid dissolved in ether was added to terminate the reaction, precipitated in cold methanol, left in the refrigerator for one day, and then filtered and dried in vacuo.
얻어진 폴리머의 조성은 무게비로(Tris-다중블럭 PEO):(PLA)가 1: 1.57이었으며, NMR상에서 락타이드 양성자 피이크는 5.50,1.56ppm에서 나타나고, 옥시에틸렌(-CH2CH2O)의 양성자 피이크는 3.64ppm에서 나타났으며, 수평분자량은 27000이었다.The obtained polymer had a weight ratio (Tris-multiblock PEO) :( PLA) of 1: 1.57, and lactide proton peaks appeared at 5.50,1.56 ppm on NMR, and were protons of oxyethylene (-CH2 CH2 O). The peak appeared at 3.64 ppm and the horizontal molecular weight was 27000.
[실시예14]Example 14
잘 건조된 반응용기에 실시예 10에서 합성한 Tris-다중블럭 PEO(MW=6600) 와 L-락타이드를 무게비로 1:2.6 사용한 것을 제외하고는 실시예 13과 같은 방법으로 반응시킨 결과, 얻어진 폴리머의 수평균 분자량은 17000이었다.The reaction was carried out in the same manner as in Example 13, except that Tris-multiblock PEO (MW = 6600) synthesized in Example 10 and L-lactide were used in a weight ratio of 1: 2.6 in a well-dried reaction vessel. The number average molecular weight of the polymer was 17000.
[실시예15]Example 15
잘 건조된 반응용기에 실시예 11에서 합성한 Tris-다중블럭 PEO(MW=9300) 와 L-락타이드를 무게비로 1:1.7 사용한 것을 제외하고는 실시예 13과 같은 방법으로 반응시킨 결과, 얻어진 폴리머의 수평균 분자량은 25000이었다.A reaction vessel was dried in the same manner as in Example 13 except that Tris-multiblock PEO (MW = 9300) and L-lactide synthesized in Example 11 were used in a weight ratio of 1: 1.7. The number average molecular weight of the polymer was 25000.
[실시예16]Example 16
잘 건조된 반응용기에 실시예 12에서 합성한 Tris-다중블럭 PEO(MW=15400) 와 L-락타이드를 무게비로 1:1 사용한 것을 제외하고는 실시예 13과 같은 방법으로 반응시킨 결과, 얻어진 폴리머의 수평균 분자량은 32000이었다.The reaction was carried out in the same manner as in Example 13, except that Tris-multiblock PEO (MW = 15400) synthesized in Example 12 and L-lactide were used in a weight ratio of 1: 1 in a well-dried reaction vessel. The number average molecular weight of the polymer was 32000.
| Application Number | Priority Date | Filing Date | Title |
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| KR1019940000270AKR0148704B1 (en) | 1994-01-10 | 1994-01-10 | Biodegradable Drug Delivery Polymer |
| US08/238,083US5548035A (en) | 1994-01-10 | 1994-05-04 | Biodegradable copolymer as drug delivery matrix comprising polyethyleneoxide and aliphatic polyester blocks |
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| KR0148704B1true KR0148704B1 (en) | 1998-08-17 |
| Application Number | Title | Priority Date | Filing Date |
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| KR1019940000270AKR0148704B1 (en) | 1994-01-10 | 1994-01-10 | Biodegradable Drug Delivery Polymer |
| KR97039395AKR0139208B1 (en) | 1994-01-10 | 1997-08-19 | A biodegradable polymer used for drug delivery device |
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